Noninvasive, nuclear imaging techniques can be used to obtain basic and diagnostic information about the physiology and biochemistry of a variety of living subjects including experimental animals, normal humans and patients. These techniques rely on the use of sophisticated imaging instrumentation that is capable of detecting radiation emitted from radiotracers administered to such living subjects. The information obtained can be reconstructed to provide planar and tomographic images that reveal distribution of the radiotracer as a function of time. Use of appropriately designed radiotracers can result in images which contain information on the structure, function and most importantly, the physiology and biochemistry of the subject. Much of this information cannot be obtained by other means. The radiotracers used in these studies are designed to have defined behaviors in vivo which permit the determination of specific information concerning the physiology or biochemistry of the subject or the effects that various diseases or drugs have on the physiology or biochemistry of the subject. Currently, radiotracers are available for obtaining useful information concerning such things as cardiac function, myocardial blood flow, lung perfusion, liver function, brain blood flow, tumor imaging, regional brain glucose and oxygen metabolism.
Compounds can be labeled with either positron or gamma emitting radionuclides. For imaging, the most commonly used positron emitting (PET) radionuclides are 11C, 18F, 15O and 13N, all of which are accelerator produced, and have half lives of 20, 110, 2 and 10 minutes, respectively. Since the half-lives of these radionuclides are so short, it is only feasible to use them at institutions that have an accelerator on site or very close by for their production, thus limiting their use. Several gamma emitting radiotracers are available which can be used by essentially any hospital in the U.S. and in most hospitals worldwide. The most widely used of these are 99mTC, 201Tl and 123I.
In the last two decades, one of the most active areas of nuclear medicine research has been the development of receptor imaging radiotracers. These tracers bind with high affinity and specificity to selective receptors and neuroreceptors. Successful examples include radiotracers for imaging the following receptor or transporter systems: estrogen, muscarinic, serotonin, dopamine, opiate, neuropeptide-Y, cannabinoid-1 and neurokinin-1.
Schizophrenia is a devastating neuropsychiatric syndrome that typically strikes in late adolescence or early adulthood. Positive or psychotic symptoms, including delusions and hallucinations, are the most apparent manifestation of the disorder. These emerge episodically and usually trigger the first hospitalization in early adulthood. Chronic aspects of the disorder include negative symptoms such as social withdrawal, flattened affect, and anhedonia as well as pervasive cognitive deficits. The latter have been closely linked to a poor function outcome and long-term prognosis (Green et al., Schizophr. Res. (2004) 72: 41-51; Harvey et al., J. Clin. Psychiatry (2004) 65: 361-372). Although dopamine D2 receptor antagonists are effective for positive symptoms, these drugs are not effective for negative and cognitive symptoms of schizophrenia, suggesting that other systems (e.g., NMDA receptor hypofunction and GABAergic hypofunction) than excessive subcortical dopaminergic activity may have also implicated in the pathophysiology of schizophrenia (Ross et al., Neuron (2006) 52: 139-153). D2 antagonists (typical antipsychotics) are known to cause extrapyramidal side effects (EPS) and hyperprolactinemia by excessive D2 receptor antagonism in the brain (Michael et al., Expert Opin. Pharmacother. (2006) 7: 1005-1016). Although atypical antipsychotics, such as olanzapine and risperidone, have a lower incidence of EPS than typical antipsychotics, these drugs still have problem of hyperprolactinemia as well as serious metabolic side effects including hyperglycemia, weight gain, diabetes, and abnormal lipid profile due to interaction with multiple neurotransmitter receptors (Michael et al., Expert Opin. Pharmacother. (2006) 7: 1005-1016). Thus novel drugs with potent efficacy against not only positive symptom but also negative and cognitive symptoms, as well as better safety profile, would be of considerable therapeutic value.
It has recently been hypothesized that inhibition of the cyclic nucleotide phosphodiesterase (PDE) will provide a new therapeutic approach to the treatment of schizophrenia (Frank et al., Nat. Rev. Drug Disc. (2000) 5: 660-670; Frank et al., Curr. Opin. Investig. Drugs (2000) 8: 54-59). PDE superfamily of enzymes was encoded by 21 genes and subdivided into 11 distinct families according to structural and functional properties (Andrew et al., Pharmacol. Rev. (2006) 58: 488-520). These enzymes metabolically inactivate the ubiquitous intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP); PDEs selectively catalyze the hydrolysis of the 3′-ester bond, forming the inactive 5′-monophosphate. On the basis of substrate specificity, the PDE families can be further classified into three groups: i) the cAMP-PDEs (PDE4, PDE7, PDE8), ii) the cGMP-PDEs (PDE5, PDE6 and PDE9), and iii) the dual-substrate PDEs (PDE1, PDE2, PDE3, PDE10 and PDE11).
PDE10 has the most restricted distribution within known PDE families; the PDE10 mRNA is highly expressed only in the brain and testis (Fujimoto et al., J. Biol. Chem. (1999) 274: 18438-18445; Loughney et al., Gene (1999) 234: 109-117; Soderling et al., Proc. Natl. Acad. Sci. USA (1999) 96: 7071-7076). PDE10 protein is also highly expressed in the brain with restricted distribution in the periphery in multiple mammalian species (Thomas et al., Brain Research (2003) 985: 113-126). In the mammalian brain, mRNA and protein of PDE10 are highly enriched in medium spiny neurons (MSNs) of the striatum (Thomas et al., Brain Research (2003) 985: 113-126; Xie et al., Neuroscience (2006) 139: 597-607; Timothy et al., J. Histochem. Cyto. (2006) 54: 1205-1213), where it regulates striatal output by its effects on both the cAMP and cGMP signaling cascades (Judith et al., Neuropharmacology (2006) 51: 374-385; Judith et al., Neuropharmacology (2006) 51: 386-396). MSNs are mainly divided into two pathways: a direct (striatonigral) pathway that expresses D1 dopamine receptors and an indirect (striatopallidal) pathway that expresses D2 dopamine receptors (Graybiel et al., Trends Neurosci. (1990) 13: 244-254; Graybiel et al., Curr. Biol. (2000) 10: 509-511). These pathways have opposing effects on striatal output. As PDE10 is expressed in both pathways, PDE10 inhibition and the resulting elevation of striatal cyclic nucleotide levels would potentially have the effects of D2 antagonism, the standard treatment for psychosis, along with D1 agonism which may minimize extrapyramidal side effect liabilities. This unique distribution and function in the brain indicates that PDE10 represents an important new target for the treatment of neurological and psychiatric disorders, in particular psychotic disorders like schizophrenia.
PET (Positron Emission Tomography) radiotracers and imaging technology may provide a powerful method for clinical evaluation and dose selection of PDE10A inhibitors. Thus, the invention herein is directed to radiolabeled PDE10A inhibitors that would be useful for exploratory and diagnostic imaging applications, both in vitro and in vivo, and for competition studies using radiolabeled and unlabeled PDE10A inhibitors.